Pharmacological disruption of the Notch transcription factor complex.

Abstract

Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.

• Authors: Rajwinder Lehal, Jelena Zaric, Michele Vigolo, Charlotte Urech, Viktoras Frismantas, Nadine Zangger, Linlin Cao, Adeline Berger, Irene Chicote, Sylvain Loubéry, Sung Hee Choi, Ute Koch, Stephen C Blacklow, Hector G Palmer, Beat Bornhauser, Marcos González-Gaitán, Yvan Arsenijevic, Vincent Zoete, Jon C Aster, Jean-Pierre Bourquin, Freddy Radtke
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 28 Pg. 16292-16301 (07 14 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32601208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• RBPJ protein, human
• Receptors, Notch
• Small Molecule Libraries

Topics

• Animals
• Apoptosis (drug effects)
• Binding Sites
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drosophila
• Drug Resistance, Neoplasm (drug effects)
• HeLa Cells
• Humans
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (chemistry, genetics, metabolism)
• Intestine, Small (drug effects, metabolism)
• Mice
• Mutation
• Phenotype
• Protein Multimerization
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Small Molecule Libraries (chemistry, pharmacology, therapeutic use)
• Transcriptional Activation (drug effects)